Insights into brain development from neurogenetic syndromes: evidence from fragile X syndrome, Williams syndrome, Turner syndrome and velocardiofacial syndrome

Abstract

Over the past few decades, behavioral, neuroimaging and molecular studies of neurogenetic conditions, such as Williams, fragile X, Turner and velocardiofacial (22q11.2 deletion) syndromes, have led to important insights regarding brain development. These investigations allow researchers to examine “experiments of nature” in which the deletion or alteration of one gene or a contiguous set of genes can be linked to aberrant brain structure or function. Converging evidence across multiple imaging modalities has now begun to highlight the abnormal neural circuitry characterizing many individual neurogenetic syndromes. Furthermore, there has been renewed interest in combining analyses across neurogenetic conditions in order to search for common organizing principles in development. In this review, we highlight converging evidence across syndromes from multiple neuroimaging modalities, with a particular emphasis on functional imaging. In addition, we discuss the commonalities and differences pertaining to selective deficits in visuospatial processing that occur across four neurogenetic syndromes. We suggest avenues for future exploration, with the goal of achieving a deeper understanding of the neural abnormalities in these affected populations.

Visuo-spatial processes as a domain-general factor impacting numerical development in atypical populations

“…However, it is interesting to highlight that impairments in visuo-spatial representations, spatial attention and processing of number and space can cascade into atypical basic numerical and arithmetical abilities (Walter, Mazaika, & Reiss, 2009).…”

Neurocognitive development of attention across genetic syndromes

“…DS, with a much higher frequency and history of research at all levels, is associated with trisomy of chromosome 21 in 95% of cases, and with well-documented behavioral difficulties and inattention in the classroom, although the cognitive underpinnings of these difficulties are less well understood (Nadel, 2003;Pennington et al, 2003). Therefore, WS, DS, and FXS provide well-defined models in which to study how relatively well-understood genetic modifications are associated with developmental trajectories of attentional difficulties and their potential impact in specific domains of cognition (e.g., social cognition; see Belmonte and Bourgeron, 2006;Bourgeron, 2009;Walter et al, 2009, for a treatment of this interdisciplinary argument across these disorders). We briefly cover the rationale for studying converging and diverging neural pathways of attention across these syndromes, to then turn to detailed cross-syndrome comparisons of attention in adults and children with these disorders.…”

“…Compelling evidence (e.g., Rivera, 2010, 2008;Kogan et al, 2004a,b) suggests that, in the non-FXS brain, FMRP is more strongly expressed in magnocellular, rather than parvocellular neurons of the lateral geniculate nucleus, and that this in turn has a differentially greater effect on the functioning and development of the dorsal stream, including parietal cortex. Multiple groups have now suggested that FMRP may be more relevant to the development of frontoparietal networks, rather than specific to it (Kogan et al, 2004a;Walter et al, 2009), as the causative mutation affects dendritic spine morphology (see Bagni and Greenough, 2005;Bassell and Warren, 2008), and results in cascading effects on the regulation of intrinsic and extrinsic neurotransmitter systems that are critical to the regulation of frontoparietal and frontostriatal circuits. These findings converge on the suggestion of dorsal stream vulnerability in FXS, just as in WS.…”

“…These two groups are therefore particularly interesting because of the association of frontoparietal deficits, and the relatively good understanding of the genetic etiology and molecular pathways involved. The comparison of WS with FXS highlights implications for thinking about dorsal stream deficits and dorsal stream vulnerability, which may be achieved through rather distinct, though possibly converging, pathways (see Walter et al, 2009, for specific suggestions of molecular candidate pathways for this convergence). Although the neurobiology of the two disorders offers a clear rationale for comparing attentional profiles in WS and FXS, very few studies have gathered data contrasting the two groups directly.…”

“…Throughout, we focus on the neurocognitive processes underlying attention by studying how their trajectories are modified across three increasingly studied genetic disorders: Williams syndrome (WS), fragile X syndrome (FXS), and Down syndrome (DS). By necessity this is a selective review of the attentional findings pertaining to these syndromes, but we recommend excellent recent reviews on their broader neurocognitive phenotypes (e.g., Karmiloff-Smith, 2009;Walter et al, 2009). In honing onto attention mechanisms, first, we provide an overview of the neurocognitive mechanisms of attention in adults and their developmental origins in typically developing (TD) brains.…”